Regulation of gene expression

p300 and CBP are thought to increase gene expression in three ways:

1. by relaxing the chromatin structure at the gene promoter through their intrinsic histone acetyltransferase (HAT) activity.
   • Jin Q, Yu LR, Wang L, Zhang Z, Kasper LH, Lee JE, Wang C, Brindle PK, Dent SY, Ge K (Jan 2011). “Distinct roles of GCN5/PCAF-mediated H3K9ac and CBP/p300-mediated H3K18/27ac in nuclear receptor transactivation”. The EMBO Journal. 30 (2): 249–62. doi:10.1038/emboj.2010.318. PMC 3025463. PMID 21131905.
2. recruiting the basal transcriptional machinery including RNA polymerase II to the promoter.
3. acting as adaptor molecules.
   •  Goodman RH, Smolik S (Jul 2000). “CBP/p300 in cell growth, transformation, and development”. Genes & Development. 14 (13): 1553–77. doi:10.1101/gad.14.13.1553. PMID 10887150. S2CID 28477108.

p300 regulates transcription by directly binding to transcription factors (see external reference for explanatory image). This interaction is managed by one or more of the p300 domains: the nuclear receptor interaction domain (RID), the CREB and MYB interaction domain (KIX), the cysteine/histidine regions (TAZ1/CH1 and TAZ2/CH3) and the interferon response binding domain (IBiD). The last four domains, KIX, TAZ1, TAZ2 and IBiD of p300, each bind tightly to a sequence spanning both transactivation domains 9aaTADs of transcription factor p53.

• Teufel DP, Freund SM, Bycroft M, Fersht AR (Apr 2007). “Four domains of p300 each bind tightly to a sequence spanning both transactivation subdomains of p53”. Proceedings of the National Academy of Sciences of the United States of America. 104 (17): 7009–14. Bibcode:2007PNAS..104.7009T. doi:10.1073/pnas.0702010104. PMC1855428. PMID17438265.; Piskacek S, Gregor M, Nemethova M, Grabner M, Kovarik P, Piskacek M (Jun 2007). “Nine-amino-acid transactivation domain: establishment and prediction utilities”. Genomics. 89 (6): 756–68. doi:10.1016/j.ygeno.2007.02.003. PMID17467953.

Enhancer regions, which regulate gene transcription, are known to be bound by p300 and CBP, and ChIP-seq for these proteins has been used to predict enhancers.

• Wang Z, Zang C, Cui K, Schones DE, Barski A, Peng W, Zhao K (Sep 2009). “Genome-wide mapping of HATs and HDACs reveals distinct functions in active and inactive genes”. Cell. 138 (5): 1019–31. doi:10.1016/j.cell.2009.06.049. PMC 2750862. PMID 19698979.
• Heintzman ND, Hon GC, Hawkins RD, Kheradpour P, Stark A, Harp LF, Ye Z, Lee LK, Stuart RK, Ching CW, Ching KA, Antosiewicz-Bourget JE, Liu H, Zhang X, Green RD, Lobanenkov VV, Stewart R, Thomson JA, Crawford GE, Kellis M, Ren B (May 2009). “Histone modifications at human enhancers reflect global cell-type-specific gene expression”. Nature. 459 (7243): 108–12. Bibcode:2009Natur.459..108H. doi:10.1038/nature07829. PMC 2910248. PMID 19295514.
• Visel A, Blow MJ, Li Z, Zhang T, Akiyama JA, Holt A, Plajzer-Frick I, Shoukry M, Wright C, Chen F, Afzal V, Ren B, Rubin EM, Pennacchio LA (Feb 2009). “ChIP-seq accurately predicts tissue-specific activity of enhancers”. Nature. 457 (7231): 854–8. Bibcode:2009Natur.457..854V. doi:10.1038/nature07730. PMC 2745234. PMID 19212405.
• Blow MJ, McCulley DJ, Li Z, Zhang T, Akiyama JA, Holt A, Plajzer-Frick I, Shoukry M, Wright C, Chen F, Afzal V, Bristow J, Ren B, Black BL, Rubin EM, Visel A, Pennacchio LA (Sep 2010). “ChIP-Seq identification of weakly conserved heart enhancers”. Nature Genetics. 42 (9): 806–10. doi:10.1038/ng.650. PMC 3138496. PMID 20729851.

Work done by Heintzman and colleagues showed that 70% of the p300 binding occurs in open chromatin regions as seen by the association with DNase I hypersensitive sites. Furthermore, they have described that most p300 binding (75%) occurs far away from transcription start sites (TSSs) and these binding sites are also associated with enhancer regions as seen by H3K4me1 enrichment. They have also found some correlation between p300 and RNAPII binding at enhancers, which can be explained by the physical interaction with promoters or by enhancer RNAs.

• Heintzman ND, Stuart RK, Hon G, Fu Y, Ching CW, Hawkins RD, Barrera LO, Van Calcar S, Qu C, Ching KA, Wang W, Weng Z, Green RD, Crawford GE, Ren B (Mar 2007). “Distinct and predictive chromatin signatures of transcriptional promoters and enhancers in the human genome”. Nature Genetics. 39 (3): 311–8. doi:10.1038/ng1966. PMID 17277777. S2CID 1595885.